7


Immune-System Disorders

As in Veterans and Agent Orange: Update 2010 (IOM, 2012, hereafter referred to as Update 2010), immune-system disorders are being addressed in a separate chapter preceding those on other adverse health outcomes. In Veterans and Agent Orange (VAO) reports prior to Update 2010—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—possible adverse health outcomes arising from disruptions of the immune system were included in the “Other Health Effects” chapter. The current committee elected to revisit comprehensively the limited epidemiologic evidence concerning association of immune disease with herbicide exposure in light of the substantial volume of toxicologic evidence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairment of the immune systems of laboratory animals.

This chapter opens with an overview of the various types of health problems that can arise from malfunctioning of the human immune system. The standard VAO sections leading to the committee’s assignment of a health outcome to a category of association follow, and they include a new tabulation of all the immune-related epidemiologic information that has been considered in this series and a synopsis of the information new in this update. The next section discusses factors that may lead the immune responses of animals exposed to the chemicals of interest (COIs) to be much more pronounced than any observed to date in humans. The chapter closes with the committee’s thoughts regarding research on the possibility that immune perturbations in humans function as a mechanistic step in the development of disease processes in other organ systems.



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7 Immune-System Disorders As in Veterans and Agent Orange: Update 2010 (IOM, 2012, hereafter referred to as Update 2010), immune-system disorders are being addressed in a separate chapter preceding those on other adverse health outcomes. In Veterans and Agent Orange (VAO) reports prior to Update 2010—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (IOM, 1996), Up- date 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—possible adverse health outcomes arising from disruptions of the im- mune system were included in the “Other Health Effects” chapter. The current committee elected to revisit comprehensively the limited epidemiologic evidence concerning association of immune disease with herbicide exposure in light of the substantial volume of toxicologic evidence of 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) impairment of the immune systems of laboratory animals. This chapter opens with an overview of the various types of health problems that can arise from malfunctioning of the human immune system. The standard VAO sections leading to the committee’s assignment of a health outcome to a category of association follow, and they include a new tabulation of all the immune-related epidemiologic information that has been considered in this series and a synopsis of the information new in this update. The next section discusses factors that may lead the immune responses of animals exposed to the chemicals of interest (COIs) to be much more pronounced than any observed to date in humans. The chapter closes with the committee’s thoughts regarding research on the possibility that immune perturbations in humans function as a mechanistic step in the development of disease processes in other organ systems. 271

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272 VETERANS AND AGENT ORANGE: UPDATE 2012 The immune system plays three important roles in the body: 1. It defends the body against infection by viruses, bacteria, and other dis- ease-producing microorganisms, known as pathogens. 2. It defends against cancer by destroying mutated cells that might otherwise develop into tumors and by providing immunity against tumors. 3. It provides resident immune cells that are specially adapted for different tissues and organs (such as microglia in the central nervous system and Kupffer cells in the liver) that help to regulate the functional activity and integrity of those tissues. To recognize the wide array of pathogens in the environment, the immune system relies on many cell types that operate together to generate immune re- sponses. Those cells arise from stem cells in the bone marrow; they are found in lymphoid tissues throughout the body; and they circulate in the blood as white blood cells (WBCs). The main types of WBCs are granulocytes, monocytes, and lymphocytes. Each type has many specialized cell populations that are respon- sible for specific functions connected to the production of specific mediators, such as immune hormones, cytokines, and other secreted factors. Imbalances in those specialized populations or in their level of functional activity can result in inadequate or improper immune responses, which may lead to pathologic out- comes. Diseases arising from immune dysfunction may be apparent immediately or observed only after an organism encounters an environmental challenge that causes immune cells to respond (such as an infection). CATEGORIES OF IMMUNE DYSFUNCTION Immune dysfunctions are in four major categories that need not be mutually exclusive: immune suppression, allergy, autoimmunity, and inflammatory dys- function (inappropriate or misdirected inflammation). Although immune suppres- sion usually is seen as an increased incidence of infections or an increased risk of cancer, allergic, autoimmune, and inflammatory disorders can be manifested as diseases that affect virtually any tissue. It is often difficult to diagnose such diseases, so they may or may not be medically categorized as immune disorders. Immune Suppression Suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer. Infection with the human immunodeficiency virus (HIV) is a well-recognized example of an acquired immune deficiency in which a specific type of lymphocyte (CD4+ T cell) is the target of the virus. The decline in the number of CD4+ T cells after HIV infection correlates with an increased incidence of infectious diseases, including fatal opportunistic infections, and with

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IMMUNE-SYSTEM DISORDERS 273 an increased incidence of several types of cancer. Treatment of cancer patients with toxic chemotherapeutic drugs suppresses the immune system by inhibiting the generation of new WBCs by the bone marrow and by blocking proliferation of lymphocytes during an immune response. Both those examples represent se- vere immune suppression in which the adverse outcome is easily detected with clinical measurements. Immune suppression can also result from exposure to chemicals in the workplace or in the environment and be manifested as recurrent infections, op- portunistic infections, a higher incidence of a specific category of infections, or a higher incidence of cancer. However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemically induced changes in immune function to increased infectious disease or cancer because many confounding factors can influence a person’s ability to combat infection. Such confounders include age, vaccination status, the virulence of the pathogen, the presence of other diseases (such as diabetes), stress, smoking, and the use of drugs or alcohol. Therefore, immunotoxicology studies are often conducted in laboratory animals to understand the scope and mechanism of chemical-induced immune suppression. Results of such studies can be used to develop biomarkers to assess effects in human populations. Infectious-disease models in animals can also be used to determine whether the pattern of disease changes with chemical exposure. Allergic Diseases The immune system sometimes responds to a foreign substance that is not pathogenic. Such immunogenic substances are called allergens. Like most immune-based diseases, allergic diseases have both environmental and genetic risk factors. Their prevalence has increased in many countries in recent decades (CDC, 2004; Linneberg et al., 2000; Simpson et al., 2008; Sly, 1999). Major forms of allergic diseases are asthma, allergic rhinitis, atopic dermatitis, and food allergy. In immediate hypersensitivity, the response to some allergens, such as pollen and bee venom, results in the production of immunoglobulin E (IgE) antibodies. Once produced, IgE antibodies bind to mast cells, specialized cells that occur in tissues throughout the body, including lung airways, the intestinal wall, and blood-vessel walls. When a person is exposed to the allergen again, it binds to the antibodies on the mast cells and causes them to release histamine and leukotrienes, which produce the symptoms associated with an allergic response. In delayed-type hypersensitivity (DTH) reactions, also known as cell-mediated immunity, other allergens, such as poison ivy and nickel, activate allergen-specific lymphocytes at the site of contact (usually the skin) that (memory T cells) release substances that cause inflammation and tissue damage. Some allergic responses, such as those to food allergens, may involve a combination of allergen-specific lymphocyte-driven and IgE-driven inflammation. Allergic responses may be man-

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274 VETERANS AND AGENT ORANGE: UPDATE 2012 ifested in specific tissues (such as skin, eyes, airways, and gastrointestinal tract) or may result in a system-wide response called anaphylaxis. Autoimmune Diseases The National Institutes of Health Autoimmune Disease Coordinating Commit­ tee recognizes 80 diseases and conditions that affect the cardiovascular, respira- tory, nervous, endocrine, dermal, gastrointestinal, hepatic, and excretory systems and are classified as autoimmune diseases (NIH Autoimmune Diseases Coordinat- ing Committee, 2005). They affect both men and women, but most affect more women than men (Fairweather et al., 2008). Genetic predisposition, age, hormone status, and such environmental factors as infectious diseases and stress are known to affect the risk of developing autoimmune diseases, and different autoimmune diseases tend to occur in the same person and to cluster in families. The existence of some autoimmune diseases is also a risk factor for the development of other immune-related diseases, such as some types of cancer (Landgren et al., 2010). Autoimmune disease is an example of the immune system’s causing rather than preventing disease: the immune system attacks the body’s own cells and tissues as though they are foreign. Inappropriate immune responses that result in autoimmune disease can be promoted by different components of the immune system (such as antibodies and lymphocytes) and can be directed against a wide variety of tissues or organs. For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn’s disease, the intestine is the target of attack; in type 1 diabetes mellitus, the i ­nsulin-producing cells of the pancreas are destroyed by the immune response; and rheumatoid arthritis arises from immune attack on the joints, but can also involve the lung, heart, and additional organs. More generalized forms of autoimmune diseases also occur. Systemic lupus erythematosus (SLE) is an autoimmune disease that has multiple target organs of immune attack. Instead, patients have a variety of symptoms that often occur in other diseases, and this makes diagnosis difficult. A characteristic rash across the cheeks and nose and sensitivity to sunlight are common symptoms; oral ulcers, arthritis, pleurisy, proteinuria, and neurologic disorders may be present. Almost all people who have SLE test positive for antinuclear antibodies in the absence of drugs known to induce them. The causes of SLE are unknown, but environ- mental and genetic factors have been implicated. Some of the environmental factors that may trigger it are infections, antibiotics (especially those in the sulfa and penicillin groups) and some other drugs, ultraviolet radiation, extreme stress, and hormones. Occupational exposures to such chemicals as crystalline silica, solvents, and pesticides have also been associated with SLE (Cooper and Parks, 2004; Parks and Cooper, 2005).

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IMMUNE-SYSTEM DISORDERS 275 Inflammatory Diseases Inflammatory diseases (also referred to as auto-inflammatory diseases) make up a more recently identified category of immune-related disorders that are char- acterized by exaggerated, excessively prolonged, or misdirected dysfunctional inflammatory responses (usually involving immune cells). Tissue disease can result from this inappropriate inflammation, which can affect virtually any organ. Examples of diseases and other conditions that are most often included in other disease categories but are also considered to be inflammatory diseases are coro- nary arterial disease, asthma, eczema, chronic sinusitis, hepatic steatosis, psoria- sis, celiac disease, and prostatitis. Inflammatory diseases often occur with one another, and this has resulted in the categorizing of different but linked inflam- matory diseases together as a single chronic inflammatory disorder (Borensztajn et al., 2011); among these are atherosclerosis and chronic pulmonary obstructive disease. Inappropriate inflammation also appears to play a role in promoting the growth of cancer (Bornschein et al., 2010; Hillegass et al., 2010; Landgren et al., 2010; Porta et al., 2010; Winans et al., 2010); examples can be seen in the higher prevalence of specific cancers in patients who have such inflammatory diseases as inflammatory bowel disease (Lucas et al., 2010; Viennot et al., 2009; Westbrook et al., 2010), prostatitis (Sandhu, 2008; Wang et al., 2009), and psoriasis (Ji et al., 2009). Ordinarily, inflammation can be advantageous in fighting infectious diseases. It is one component of the normal host response to infection and is mediated by innate immune cells. Inflammatory responses have evolved to speed the traffick- ing of macrophages, granulocytes, and some lymphocytes to the area of infection, where they produce toxic metabolites that kill pathogens. Interactions among in- nate immune cells and epithelial and endothelial cells are important in regulating the magnitude of inflammation. However, improperly regulated inflammation can contribute to diseases that arise in nonlymphoid tissues, such as the lungs, skin, nervous system, endocrine system, and reproductive system. CONCLUSIONS FROM VAO AND PREVIOUS UPDATES The following comments are restricted to findings related to the immune sys- tem that occur after adult human exposure. For a discussion of potential effects on the immune system arising from early-life (such as perinatal) exposures (which would not be directly applicable to the Vietnam veterans who are the target of this report), see Chapters 4 and 9. Studies that served as the basis of prior updates of VAO are shown in Table 7-1. Vietnam Veterans A handful of the direct studies of veterans listed in Table 7-1 reported a statistically significant difference in a single immune measure (Kim et al., 2003;

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276 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 7-1  Selected Epidemiologic Studies—Immune Effects in Adult Humans (Shaded Entries Are New Information for This Update) Study Population Exposure/Results Reference VIETNAM VETERANS US Air Force Health Study—Operation All COIs Ranch Hand veterans vs SEA veterans Participants in 1997 examination cycle, No change in surface markers for Michalek Operation Ranch Hand veterans vs B and T cells, no change in serum et al., comparisons (incidence) Ig, no change in autoantibodies 1999a (antinuclear antibody, smooth muscle autoantibody, parietal cell autoantibody, rheumatoid factor, and monoclonal immunoglobulins) and no dose-related change in DTH response Participants in 1987 examination cycle, No change in surface markers for B and Wolfe et Operation Ranch Hand veterans vs T cells al., 1990 comparisons (morbidity) Participants in 1985 examination cycle, No change in surface markers for B and Wolfe et Operation Ranch Hand veterans vs T cells al., 1985 comparisons (morbidity and mortality) US CDC Vietnam Experience Study— All COIs Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed Morbidity—Deployed vs nondeployed No differences in infections, no changes CDC, in B and T cell-surface markers, WBC 1988b counts, or circulating serum Ig Mortality (1965–2000) No increase in infectious or parasitic Boehmer diseases et al., 2004 US VA Cohort of Monozygotic Twins All COIs Physical health—morbidity Increase in skin conditions of unknown Eisen et etiology, no increase in blood disorders al., 1991 US American Legion Cohort All COIs Physical health and reproductive Increase in skin conditions and arthritis Stellman outcomes et al., 1988 State Studies of US Vietnam Veterans All COIs Michigan Vietnam Veterans (deployed Increased mortality from infectious Visintainer vs nondeployed) (including parasitic) diseases et al., 1995

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IMMUNE-SYSTEM DISORDERS 277 TABLE 7-1  Immune Effects in Adult Humans, continued Study Population Exposure/Results Reference New Jersey Agent Orange Commission Depressed response to tetanus in DTH Kahn et tests, decrease in CD4 and SmIg+ B al., 1992 cells Texas Agent Orange Advisory Increase in percentage of active T Newell, Committee rosette-forming cells 1984 Sample of 1,000 Male Australian All COIs Vietnam Veterans–prevelance Australian Vietnam Veterans— Increase in hay fever, increases in O’Toole et longitudinal cohort study of 67 infectious and parasitic diseases, al., 2009 conditions in randomly selected increase in arthritis Vietnam veterans vs general population Australian Conscripted Army National All COIs Service (18,940 deployed vs 24,642 nondeployed) 1983–1985—Australian Vietnam Increase in hay fever, increases in CDVA, Veterans—longitudinal cohort study infectious and parasitic diseases, 1997b of 67 conditions in randomly selected increase in arthritis Vietnam veterans vs general population Korean Vietnam Veterans All COIs Immunotoxicologic study Increase in IgE and IL-4, decrease in Kim et al., IgG1 and IFN-gamma, no change in 2003 lymphocyte counts Vietnamese Vietnam Veterans All COIs Antinuclear and sperm autoantibodies No change in autoantibodies to sperm, Chinh et antinuclear bodies al., 1996 OCCUPATIONAL STUDIES IARC Phenoxy Herbicide Cohort— Chlorophenoxy herbicides/General Saberi Subset of Dutch workers (n = 85) from reduction in most analyte levels with Hosnijeh 2 plants that produced and formulated the strongest effects for fractalkine, et al., chlorophenoxy herbicides (high exposure fibroblast growth factor (FGF2), and 2012 = 47, low exposure = 38); serum transforming growth factor alpha collected 30 yrs after exposure (TGF-α) IARC Phenoxy Herbicide Cohort— Chlorophenoxy herbicides/Negative Saberi Dutch workers from 2 plants that correlation between TCDD exposure Hosnijeh produced and formulated chlorophenoxy and markers of humoral immunity, et al., herbicides (Plant A, n = 1,167; Plant B, except perhaps for C4 2012 n = 1,143). continued

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278 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 7-1  Immune Effects in Adult Humans, continued Study Population Exposure/Results Reference IARC Phenoxy Herbicide Cohort— Dioxins, phenoxy herbicides German production workers (2,479 workers at 4 plants, in IARC as of 1997) Cross-sectional study of 153 male TCDD (during production of TCP): Benner et workers in six chemical plants in DTH responses not correlated with al., 1994 Germany dioxin concentration; slight decrease in IgM was reported with increasing dioxin exposure; overall lymphoid counts not different German production workers at BASF Focus on TCDD Ludwigshafen Plant—BASF Cleanup workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC) 138 surviving workers from a larger TCDD: Among 14 immune measures; Ott et al., cohort of 254 exposed workers after regression analysis of TCDD 1994 an accident in a BASF TCP production concentration suggested marginal facility positive associations with IgG, IgA, C3, and C4; marginal reductions in some lymphocyte population were also reported IARC Phenoxy Herbicide Cohort— Dioxins, 2,4,5-T; 2,5-DCP; 2,4,5-TCP German production workers at Boehringer-Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) Updated and expanded evaluation of TCDD (or “TCDD toxic equivalents” Neubert et 158 workers in a German chemical from PCDD/PCDF): No differences al., 2000 plant with differing exposure studied in in serum Ig or cytokine (IL1, IL6, two trials TNF-alpha) 19 highly exposed chemical workers vs TCDD (in chemical plant): In subset of Ernst et 28 unexposed controls in two chemical leukocytes, increase in CD8+ memory al., 1998 plants in Hamburg, Germany T cells and decrease in naïve T cells (CD45RA+) after TCDD exposure, as was stimulated IFN-gamma production from whole blood cultures associated with TCDD exposure

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IMMUNE-SYSTEM DISORDERS 279 TABLE 7-1  Immune Effects in Adult Humans, continued Study Population Exposure/Results Reference 192 workers in a German pesticide TCDD (or TEQs from PCDD/PCDF Jung et al., plant, including 29 highly exposed exposure): No significant changes 1998 and 28 controls compared for immune in TCDD and lymphocyte subsets, functional tests antibody responses to vaccination, lymphocyte proliferation, or autoantibody production; decrease in chromate resistance of PHA-stimulated lymphocytes in highest exposure group Comparison of 11 2,4,5-trichlorophenol TCDD: No differences in any Tonn et production workers 20 years after lymphoid subset or in mitogen-induced al., 1996 exposure vs 10 unexposed age-matched proliferation; TCDD exposure was workers in the same company associated with decreases in MLR response and in stimulation with IL-2 in vitro Examination of eight trichlorophenol TCDD: Reduced gamma globulins Jansing production workers who developed in the most-exposed workers; no and Korff, chloracne and were reexamined 15–25 significant effects on T4, T8 ratios. 1994 years after initial exposure 89 volunteers involved in TCDD (or equivalents via PCDD/PCDF Neubert et decontamination work at a chemical exposure): Potentially complicated by al., 1993, plant in Hamburg, Germany; no control age differences among the compared 1994 population groups; only subtle, clinically nonsignificant changes were seen among immune-cell surface markers in a comparison of higher exposed vs low- exposed to moderately exposed workers NIOSH Cohort (current and former Dioxins, phenoxy herbicides workers from chemical plants in New Jersey and Missouri, 2 of the 12 plants included in the NIOSH Mortality Study) Cross-sectional study of 259 TCDD- TCDD (exposure in a chemical plant): Halperin et exposed 2,4,5-trichlorophenate (and No significant changes in serum Ig or al., 1998 its derivatives) workers (mean serum major leukocyte categories; TCDD TCDD, 223 ppt) and 243 unexposed associated with decreased circulating residential controls (mean serum TCDD, CD26 cells (activated T cells) 6 ppt) 1987 cross-sectional study of 281 TCDD (as a contaminant in chemical Sweeney chemical-plant workers in NJ and MO production): Increase in TCDD et al., at least 15 years after exposure vs 260 associated with a decrease in CD3/Ta1 1997/1998 unexposed controls (helper lymphocytes) cells Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts) continued

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280 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 7-1  Immune Effects in Adult Humans, continued Study Population Exposure/Results Reference EUROPIT Study—Prospective Pesticide factories (not specifically Baranska multicenter cohort study (Bulgaria, TCDD): Reduced antibody responses to et al., 2008 Finland, Italy, The Netherlands) of hepatitis B vaccination among exposed 238 pesticide-exposed workers vs 198 workers carrying a specific IL-1 allele unexposed workers OCCUPATIONAL—HERBICIDE- USING WORKERS (not related to IARC sprayer cohorts) Agricultural Health Study (AHS)— Pesticides/herbicides prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/ farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010 Comparison from the AHS of 534 cases Both high-level acute pesticide exposure Beseler et of self-reported physician-diagnosed (OR = 2.6, 95% CI 1.7–3.8) and al., 2008 depression vs 17,051 controls cumulative pesticide exposure (OR = 1.5, 95% CI 1.2–2.0) were positively associated with increase in depression 29,074 female spouses of pesticide Depression was significantly associated Beseler et applicators in the AHS with pesticide poisoning (OR = 3.3, al., 2006 95% CI 1.7–6.2) but not with lower cumulative exposure Nested case-control study of rheumatoid No strong risk factors were identified De Roos et arthritis in agricultural families (57,000 for pesticide mixing or application or al., 2005b pesticide applicators and their spouses) for any specific class of pesticides in the AHS of rheumatoid arthritis Other Studies of Herbicide-Using Workers Longitudinal study of 10 farmers during 2,4-D and MCPA formulations: Faustini et 1994 within 7 days before and 1–12 Decreases in percentages of CD4, CD8, al., 1996 days and 50–70 days after exposure CTL, CD8-DR, and NK cells and in NK activity and mitogen-stimulated lymphoproliferation; CD4:CD8 ratio was unaltered; CD3 and CD8 percentages had recovered by the second assessment period; no significant correlations between immune changes and amount of pesticides applied

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IMMUNE-SYSTEM DISORDERS 281 TABLE 7-1  Immune Effects in Adult Humans, continued Study Population Exposure/Results Reference ENVIRONMENTAL STUDIES Seveso Cleanup Workers TCDD Prospective study using analysis of No differences in WBC counts and Ghezzi et samples from 36 cleanup workers (divided platelet counts al., 1982 into three groups based on time spent in the contamination area); pre-employment samples and samples after 9 months were analyzed for comparison with samples from 31 nonexposed workers Seveso, Italy, Residential Cohort— TCDD Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) Study of 101 chloracne cases vs 211 Persistent increase in TCDD in Baccarelli controls 20 years after the accident; chloracne cases; younger people seemed et al., relatively low statistical power was to be more susceptible; no major trends 2005b available because the study examined in disease occurrence the occurrence of individual diseases Study of 62 people from a highly Plasma concentration of TCDD was Baccarelli exposed zone and 53 from determined; multivariate regression et al., 2002 noncontaminated areas 20 years after analysis showed significant decrease the accident in plasma IgG with increasing TCDD concentration and no changes in IgM, IgA, or C3 45 children (3–7 years of age) living No differences in serum IG, mitogen Pocchiari in exposed areas vs 45 nonexposed responses of lymphocytes (PHA and et al., 1979 children as controls pokeweed), or percentage of rosette- forming lymphocytes Times Beach (MO) Cohort TCDD Regression analysis used for No TCDD–DTH response relationships Webb et comparisons among 41 exposed people were reported; no change in mitogen al., 1989 for adipose-tissue, TCDD vs immune responsiveness; some serum markers measures; three exposed groups defined (A/G ratio and serum IgG) were by tissue dioxin affected 82 people in more highly contaminated No differences in DTH response or Webb et areas vs 40 in low-risk exposure areas T-cell subsets (T4/T8) al., 1987 as controls 80 people in highly contaminated areas No differences in DTH induration or Stehr et vs 40 controls in lower-risk areas T-cell subset analysis (T4/T8) al., 1986 continued

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288 VETERANS AND AGENT ORANGE: UPDATE 2012 Fiorito et al., 2010, 2011; Head and Lawrence, 2009; Jin et al., 2010; ­ anchez et S al., 2010). It is consistent with its immunosuppressive effects that TCDD exposure suppresses the allergic immune response of ­ odents; this in turn results in decreased r allergen-associated pathologic lung conditions and has recently been shown to suppress the development of experimental ­ utoimmune disease ­Quintana et al., a ( 2008), to induce the suppression of auto­ mmune ­ veoretinitis (Zhang et al., 2010), i u and to affect colitis (Takamura et al., 2011), arthritis (­ akahama et al., 2011), and N inflammatory lung diseases, such as silicosis (Beamer et al., 2012). A recent study of 18 people who had allergic asthma, 17 people whose asthma was controlled, and 12 controls showed that the plasma concentrations of IL-22 and the expres- sion of the AHR in peripheral blood mononuclear cells was associated with the severity of allergic asthma; this finding strengthened the possibility that the AHR is involved in allergic asthma, thereby implying a role for dioxin exposure in this condition (Zhu et al., 2011). Thus, depending on the disease, TCDD exposure could exacerbate or ameliorate symptoms. Recent attention has focused on the ability of the AHR to induce regulatory T cells, or Tregs (Kerkvliet, 2012; Marshall and Kerkvliet, 2010). Tregs have po- tent suppressive activity in the immune system, and their inappropriate induction by TCDD could account for much of the immune suppression. AHR activation in dendritic cells has also been shown to promote the development of Tregs by inducing tryptophan metabolism. AHR activation in B cells can directly disrupt the production of antibodies (Sulentic and Kaminski, 2011). The recent demon- stration that AHR activation by TCDD leads to the development of Tregs helps to explain the diversity of effects seen after exposure to TCDD (Funatake et al., 2008; Kerkvliet, 2012; Marshall et al., 2008; Quintana et al., 2008; Stockinger et al., 2011; Yamamoto and Shlomchik, 2010). Recent data indicate that the AHR pathway plays an integral role in B-cell maturation, and that TCDD and DLC exposure may alter the function of these cells and result in critical changes in the immune response. Suppression of the immune response by TCDD and similar compounds in mice has been known for over 30 years, but the effect on human cells is less clear. Some recent reports indicate that TCDD and DLC elicit similar effects in humans. Activation of non-transformed human B cells results in an increase in expression of the AHR, indicating that this pathway has a role in normal B-cell function (Allan and Sherr, 2010). Furthermore, treatment of those cells with B[a]P suppresses B-cell differentiation. Lu et al. (2010) demonstrated that although human B cells ap- peared less responsive to TCDD in increasing expression of AHR battery genes, the ability of TCDD to decrease IgM production was similar in both mouse and human B cells. In addition, data from human hemopoietic stem cells (HSCs) and knockout AHR mouse models show that the AHR is critical in HSC maturation and differentiation (Fracchiolla et al., 2011; Singh et al., 2011). TCDD not only alters HSC maturation but also alters proliferation and migration in vivo and in

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IMMUNE-SYSTEM DISORDERS 289 vitro (Casado et al., 2011), and this indicates that exposure may have multiple effects on immune-cell function. SYNTHESIS Immune Suppression One would expect exposure to substantial doses of TCDD to result in im- mune suppression in Vietnam veterans. However, several studies of various measures of human immune function failed to reveal consistent correlations with TCDD exposure, probably because the exposures were inadequate to produce im- mune suppression or because the characteristics measured were not among those most relevant with respect to biologic plausibility. No clear pattern of an increase in infectious disease has been documented in the studies of veterans exposed to TCDD or to the herbicides used in Vietnam. However, three occupational-expo- sure studies provide some support for the idea that exposure to TCDD may result in an altered immune response to some exposures and an increased frequency of infections. The study of a single highly exposed person (Brembilla et al., 2011) confirmed TCDD-associated changes in immune measures that may not be ap- plicable to people whose exposure was considerably lower. Immune alteration and the frequency and duration of specific types of infections should therefore be a focus of future studies. Suppression of the immune response by TCDD might increase the risk of some kinds of cancer in Vietnam veterans, but there is no evidence to support the connection. Allergic and Autoimmune Diseases Epidemiologic studies have been inconsistent with regard to TCDD’s influ- ence on IgE production in humans. No human studies have specifically addressed the influence of TCDD on autoimmune disease, but several animal studies have shown that TCDD suppresses the development of autoimmune diseases. In study- ing postservice mortality, Boehmer et al. (2004) found no increase in deaths of Vietnam veterans that could be attributed to immune-system disorders. There is no experimental evidence to support that finding, but increased inflammatory responses could be involved. The study of people who had allergic asthma or controlled asthma strengthened the data and suggested that the AHR (and thus dioxin exposure) is involved in the disease (Zhu et al., 2011). Future studies are needed to determine a potential mechanism of TCDD-induced allergic and auto- immune disease, including rheumatoid arthritis. Few effects of phenoxy herbicide or cacodylic acid exposure on the im- mune system have been reported in animals or humans, and no clear association between such exposure and autoimmune or allergic disease has been found.

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290 VETERANS AND AGENT ORANGE: UPDATE 2012 Exposure of laboratory animals to phenoxy herbicides or cacodylic acid has not been associated with immunotoxicity. Inflammatory Diseases There are no human data on the potential for dioxin or the herbicides of inter- est to induce dysregulation of inflammation that could contribute to an increased risk of inflammation-associated diseases. Possible associations involving infectious or inflammation-related diseases should be a focus for the future. Examples of earlier studies whose results support the occurrence of such adverse outcomes are Baccarelli et al. (2002), Baranska et al. (2008), Beseler et al. (2008), Oh et al. (2005), O’Toole et al. (2009), Tonn et al. (1996), and Visintainer et al. (1995). CONCLUSIONS On the basis of the evidence reviewed here and in previous VAO reports, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and specific infectious, allergic, or autoimmune diseases. TRANSLATION BETWEEN ANIMAL AND HUMAN STUDIES Animal studies and in vitro studies with human cells and cell lines are im- portant ways of trying to understand underlying biologic mechanisms associated with immunotoxic and other responses to xenobiotics, which are “foreign” sub- stances that do not normally occur in biologic systems. However, as discussed above, despite the vast array of data supporting the immunotoxicity of TCDD in laboratory animals, little evidence from studies of Vietnam veterans or other human populations suggests that TCDD or the herbicides of concern produce immune alterations. Many factors must be considered in examining the relevance of animal and in vitro studies to human disease and disease progression, and they are discussed in Chapter 4. Here, we present the factors that are probably most important in considering differences between the results of laboratory studies and the findings of observational epidemiologic studies. Magnitude and Timing of Exposure In general, the TCDD exposures used in animal studies have been orders of magnitude higher than exposures that Vietnam veterans are likely to have received during military service. It is well known that the immune system is highly susceptible to xenobiotic exposure during critical stages of development,

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IMMUNE-SYSTEM DISORDERS 291 such as gestation, and that primary immune responses are easier to alter than are secondary immune responses. In vivo studies show that exposure to antigens may be important, so the timing of antigen exposure relative to TCDD exposure may be an important variable. Genetic Susceptibilities Human immune diseases are likely to have complex etiologies and to be un- der the influence of numerous genes and gene–environment interactions (­ ietert D et al., 2010). Differences in AHR affinity between species may be a factor in animal-to-human extrapolation. For example, many strains of mice (AHRb) are known to exhibit greater susceptibility of CYP1A1 induction and immune sup- pression than are other strains (AHRd). In contrast, a simple single-haplotype dif- ference in susceptibility to TCDD has not been observed in humans. Rats appear to be more similar to the resistant AHRd phenotype of mice in their sensitivity to TCDD. Indeed, it is difficult to produce immune suppression in rats with TCDD because of that, and there probably are other genetic reasons as well. Sex Differences There are well-known differences in susceptibility to xenobiotic exposures between male and female animals. There are probably multiple reasons for the differences, some of which may pertain to immunomodulation by sex steroids. Similarly, evidence suggests that specific immune-based health risks in humans have important sex differences. For example, women generally are much more susceptible than are men to the development of several autoimmune diseases; such differences in humans may result from a combination of genetic factors and environmental exposures. That has ramifications for future studies. In consider- ing the potential effects of Agent Orange on the immune system and the risk of disease, sex-based differences in chemically induced adverse immune outcomes need to be investigated. Future studies should ensure that—whether in animal models or in human studies—gene-specific or sex-specific immune effects are able to be evaluated with sufficient statistical power to support distinctions. Stress Stress is a well-known modifier of human immune responses. It is an ever- present variable that is difficult to assess or control for in epidemiologic studies.

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